Project Summary Amyloid-? (A?) plaques and tau neurofibrillary tangles, as well as neuronal death, are the pathologic hallmarks of Alzheimer?s disease (AD). Therapeutic efforts focused on A? have thus far failed, underscoring the urgent need for alternate approaches, particularly those that can target early AD. Aberrant tau in the locus coeruleus (LC), the major noradrenergic nucleus in the brain that regulates attention, arousal, stress responses, and cognition, is the earliest detectable AD-like neuropathology in the human brain, and thus represents a potential therapeutic target. However, we do not know why LC neurons are selectively vulnerable to developing early tau pathology and degenerating later in disease, nor whether the LC might seed the stereotypical spread of tau pathology to the rest of the brain. Based on a wealth of cell culture and in vivo preliminary data, we propose to test the hypothesis that the toxic norepinephrine (NE) metabolite DOPEGAL activates asparagine endopeptidase (AEP), which cleaves tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of tau pathology to the forebrain. In Aim 1, we will examine the impact of DOPEGAL on tau pathology and toxicity in primary mouse LC neurons using various knockout, viral vector, and pharmacological tools to manipulate NE metabolism and AEP. In Aim 2, we will determine whether DOPEGAL-induced AEP cleavage of tau is necessary for toxicity in vivo by exploring the effects of P301S tau overexpression in the LC on DOPEGAL levels, pathogenic tau accrual, and noradrenergic function following genetic or pharmacological inhibition of the NE-DOPEGAL-AEP-Tau pathway. In Aim 3, we will test the contribution of the NE-DOPEGAL-AEP-Tau pathway and neuronal activity on the spread of pathogenic tau from the LC to the forebrain. Completion of these experiments will reveal the role of DOPEGAL and AEP in the selective vulnerability of LC neurons in AD and lay the foundation for the development of LC/AEP-based therapies that retard progression of the disease.